Thymic Epithelial Cells Responsible for Impaired Generation of NK-T Thymocytes in Alymphoplasia Mutant Mice

Konishi, Jun; Iwabuchi, Kazuya; Iwabuchi, Chikako; Ato, Manabu; Nagata, Junichi; Onoe, K.; Nakagawa, Kenta; Kasai, Mari; Ogasawara, Kunio; Kawakami, Kazuyoshi; Onoé, Kazunori

doi:10.1006/cimm.2000.1723

Cited by 10 publications

(8 citation statements)

References 43 publications

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“…The results of BM chimera clearly indicate the significance of NIK in host cells for NKT-ab cells [12][13][14][15] (and this study) or cd T cells 22 for their efficient maturation. In our unpublished study using TCR-transgenic mice, it was suggested that the positive selection of conventional T cells bearing particular TCR was attenuated in an aly/aly background, and here again, absence of NIK in nonhaematopoietic cells was found to be responsible for it (K. Eshima and K. Iwabuchi, manuscript in preparation).…”

Section: Discussionsupporting

confidence: 69%

“…We previously reported that the number and proportion of NKT-ab cells are severely reduced in aly/aly mice, and that the defects may reside in TECs. 12,15 In the present study, we extended this notion by exploring the potential difference in NIK dependence among the subsets of NKT cells. We also examined the requirement of NIK in the function of mature NKT-ab cells by investigating NIK-defected NKT-ab cells.…”

Section: Discussionmentioning

confidence: 98%

“…[12][13][14] The deficiency of NKT-ab cell generation in aly/aly mice was suggested to be caused by impaired formation of medullary thymic epithelial cells. 15 However, although critical dependence on NIK of iNKT cell generation was clearly shown, 13,14 the differentiation of other NKT subsets in the absence of NIK has yet to be investigated.…”

Section: Introductionmentioning

confidence: 99%

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Differential dependence on nuclear factor‐κB‐inducing kinase among natural killer T‐cell subsets in their development

et al. 2015

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SummaryNatural killer T cells (NKT cells) are comprised of several subsets. However, the possible differences in their developmental mechanisms have not been fully investigated. To evaluate the dependence of some NKT subpopulations on nuclear factor-jB-inducing kinase (NIK) for their generation, we analysed the differentiation of NKT cells, dividing them into subsets in various tissues of alymphoplasia (aly/aly), a mutant mouse strain that lacks functional NIK. The results indicated that the efficient differentiation of both invariant NKT (iNKT) and non-iNKT cells relied on NIK expression in non-haematopoietic cells; however, the dependence of noniNKT cells was lower than that of iNKT cells. Especially, the differentiation of CD8 + non-iNKT cells was markedly resistant to the aly mutation.The proportion of two other NKT cell subsets, NK1.1 + cd T cells and NK1.1 À iNKT cells, was also significantly reduced in aly/aly mice, and this defect in their development was reversed in wild-type host mice given aly/ aly bone marrow cells. In exerting effector functions, NIK in NKT-ab cells appeared dispensable, as NIK-deficient NKT-ab cells could secrete interleukin-4 or interferon-c and exhibit cytolytic activity at a level comparable to that of aly/+ NKT-ab cells. Collectively, these results imply that the NIK in thymic stroma may be critically involved in the differentiation of most NKT cell subsets (although the level of NIK dependence may vary among the subsets), and also that NIK in NKT-ab cells may be dispensable for their effector function.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Differential dependence on nuclear factor‐κB‐inducing kinase among natural killer T‐cell subsets in their development

et al. 2015

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“…Populations of these scattered mononuclear cells were not identified in the present study. They might be primitive T cells such as natural killer cells and large granular lymphocytes because of a deficiency of mature T and B cells in aly/aly mice [Konishi et al, 2000;Coles et al, 2006]. Moreover, it was also notable that the regeneration of some pancreatic ducts was observed in areas of the lymphocytic infiltration and the exocrine degeneration.…”

Section: Discussionmentioning

confidence: 99%

Sequential Histopathology of Pancreatic Tissues in <i>aly/aly </i>Mice

Nakamura¹,

Yi²,

Terayama³

et al. 2007

Cells Tissues Organs

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C57BL/6J strain mice carrying the homozygous autosomal recessive mutation alymphoplasia (aly) lack peripheral lymph nodes and Peyer’s patches and exhibit chronic infiltration of lymphocytes into various organs. Pancreatitis, one of the inflammatory lesions, is considered to be of autoimmune origin; however, the target autoantigens have not yet been determined. In this study, pancreatic tissues of male aly/aly mice and wild-type mice at 1–65 weeks of age were light- and electron-microscopically examined to investigate when and how pancreatitis develops. The results showed that macrophages had first appeared and remained in the lymphatic lumen at 3 weeks of age and then a lot of eosinophilic granulocytes infiltrated into the interlobular connective tissues at 5 weeks of age. After the subsidence of eosinophilic inflammation, macrophages and B220+ cells appeared at the perivascular tissues at 9 weeks of age. Thereafter, both CD4+ and CD8+ cells finally participated in the interstitial inflammation from 11 weeks of age. It was noted that these leukocytes had infiltrated into the perivascular interstitium rather than the parenchymal tissues during the course of pancreatitis, although a large parenchymal area was finally degenerated and replaced by adipose tissue.

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“…The subsequent maturation and acquisition of NK markers by CD44 high NK1.1 Ϫ V␣14i NKT cells is strictly dependent upon T-bet, which may also control the expression of CD122 (and hence IL-15 responsiveness) characteristic of this population (17,18). To complicate matters further, there is a clear (although still poorly defined) requirement for stromal cells in V␣14i NKT cell development (19), which involves the NF-B pathway (20,21).…”

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confidence: 99%

Selective Requirement for c-Myc at an Early Stage of Vα14i NKT Cell Development

Mycko

Ferrero

Wilson

et al. 2009

The Journal of Immunology

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Vα14 invariant (Vα14i) NKT cells are a subset of regulatory T cells that utilize a semi-invariant TCR to recognize glycolipids associated with monomorphic CD1d molecules. During development in the thymus, CD4+CD8+ Vα14i NKT precursors recognizing endogenous CD1d-associated glycolipids on other CD4+CD8+ thymocytes are selected to undergo a maturation program involving sequential expression of CD44 and NK-related markers such as NK1.1. The molecular requirements for Vα14i NKT cell maturation, particularly at early developmental stages, remain poorly understood. In this study, we show that CD4-Cre-mediated T cell-specific inactivation of c-Myc, a broadly expressed transcription factor with a wide range of biological activities, selectively impairs Vα14i NKT cell development without perturbing the development of conventional T cells. In the absence of c-Myc, Vα14i NKT cell precursors are blocked at an immature CD44lowNK1.1− stage in a cell autonomous fashion. Residual c-Myc-deficient immature Vα14i NKT cells appear to proliferate normally, cannot be rescued by transgenic expression of BCL-2, and exhibit characteristic features of immature Vα14i NKT cells such as high levels of preformed IL-4 mRNA and the transcription factor promyelocytic leukemia zinc finger. Collectively our data identify c-Myc as a critical transcription factor that selectively acts early in Vα14i NKT cell development to promote progression beyond the CD44lowNK1.1− precursor stage.

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Thymic Epithelial Cells Responsible for Impaired Generation of NK-T Thymocytes in Alymphoplasia Mutant Mice

Cited by 10 publications

References 43 publications

Differential dependence on nuclear factor‐κB‐inducing kinase among natural killer T‐cell subsets in their development

Differential dependence on nuclear factor‐κB‐inducing kinase among natural killer T‐cell subsets in their development

Sequential Histopathology of Pancreatic Tissues in <i>aly/aly </i>Mice

Selective Requirement for c-Myc at an Early Stage of Vα14i NKT Cell Development

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